Mercaptoalkanoylamino and acylmercaptoalkanoylamino benzoxazepines and benzothiazepines

- E. R. Squibb & Sons, Inc.

Compounds of the formula ##STR1## wherein X.sub.1 is ##STR2## are disclosed. These compounds possess inhibitory activity against angiotensin converting enzyme and neutral endopeptidase and thus useful as cardiovascular agents.

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Claims

1. A compound of the formula (I) ##STR69## and pharmaceutically acceptable salts thereof wherein: R.sub.1 is hydrogen, ##STR70## or R.sub.18 --S--; R.sub.2 and R.sub.19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl-(CH.sub.2).sub.m --, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m -- or R.sub.2 and R.sub.19 taken together with the carbon atom to which they are attached complete a cycloalkyl ring or a benzofused cycloalkyl ring;

n is zero or one;
m is zero or an integer from 1 to 6;
R.sub.3 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.m --;
R.sub.18 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, heteroaryl-(CH.sub.2).sub.m -- or --S--R.sub.18 completes a symmetrical disulfide wherein R.sub.18 is of the formula (II) ##STR71## X.sub.1 is of the formula (VI) ##STR72## (VII) ##STR73## R.sub.6 and R.sub.10 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --;
R.sub.7 and R.sub.11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl --(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m -- or R.sub.6 and R.sub.7 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons;
b is zero or one;
s is zero, one or two;
Y.sub.1 is --O--or ##STR74## Y.sub.4 is --O--; R.sub.12 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, heteroaryl-(CH.sub.2).sub.m --, ##STR75## R.sub.14 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R.sub.15 is hydrogen, lower alkyl, lower alkoxy or phenyl;
R.sub.16 is lower alkyl or aryl-(CH.sub.2).sub.m --;
the term "alkyl" refers to straight and branched chain radicals having one to seven carbon atoms;
the term "substituted alkyl" refers to such straight or branched chain radicals of 1 to 7 carbons wherein one or more hydrogens have been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.2, lower alkoxy, lower alkylthio or carboxy;
the term "alkenyl" refers to straight or branched chain radicals of 3 to 7 carbon atoms having one or two double bonds;
the term "substituted alkenyl" refers to such straight or branched radicals of 3 to 7 carbons having one or two double bonds wherein a hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.2, lower alkoxy, lower alkylthio, or carboxy;
the term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms;
the term "aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl;
the term "substituted aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl having a substituent selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl), and --N(lower alkyl).sub.2, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino;
the term "heteroaryl" refers to unsaturated monocyclic rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms is four or less and all other atoms in the ring are C and bicyclic rings wherein the five or six membered ring as defined above is fused to a phenyl or pyridyl ring, said heteroaryl ring is attached by way of an available carbon or nitrogen atom; and said monocyclic or bicyclic ring can be substituted at an available carbon atom by lower alkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can be substituted at an available nitrogen atom by benzyloxymethyl, p-toluene sulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl or benzhydryl;
the term "lower alkyl" refers to straight or branched chain radicals having one to four carbons;
the term "substituted lower alkyl" refers to such straight or branched chain radicals having one to four carbons wherein one hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.2, lower alkoxy, lower alkylthio, or carboxy;
the terms "lower alkoxy" and "lower alkylthio" refer to such lower alkyl groups as defined above attached to an oxygen or sulfur; and
the term "halo" refers to chloro, bromo, fluoro, and iodo.

2. A compound of claim 1 wherein:

X.sub.1 is of the formula ##STR76##

3. A compound of claim 2 wherein:

R.sub.1 is hydrogen, ##STR77## or R.sub.18 --S--; R.sub.3 is lower alkyl of 1 to 4 carbons or phenyl;
R.sub.18 is lower alkyl of 1 to 4 carbons;
n is zero or one;
R.sub.2 is aryl-CH.sub.2 --, substituted aryl-CH.sub.2 --, heteroaryl-CH.sub.2 --, or straight or branched chain alkyl of 1 to 7 carbons; and
R.sub.19 is hydrogen.

4. A compound of claim 3 wherein:

Y.sub.1 is O or S;
R.sub.6 and R.sub.7 are both hydrogen or R.sub.6 is lower alkyl of 1 to 4 carbons and R.sub.7 is hydrogen;
R.sub.10 and R.sub.11 are both hydrogen or one is hydrogen and the other is lower alkyl of 1 to 4 carbons;
b is zero; and
R.sub.12 is hydrogen or lower alkyl of 1 to 4 carbons.

5. A compound of claim 4 wherein:

Y.sub.1 is O.

6. A compound of claim 5 wherein

R.sub.1 is hydrogen;
n is zero;
R.sub.2 is benzyl, (2-thienyl)methyl, or straight or branched chain alkyl of 1 to 5 carbons.

9. A compound of claim 4 wherein:

Y.sub.1 is S.

10. A compound of claim 9 wherein

R.sub.1 is benzyl, (2-thienyl)methyl, or straight or branched chain alkyl of 1 to 5 carbons.

12. A compound of claim 1 wherein:

X.sub.1 is of the formula (VII) ##STR78##

13. A compound of claim 12 wherein:

Y.sub.4 is O;
R.sub.1 is hydrogen, ##STR79## or R.sub.18 --S--; R.sub.3 is lower alkyl of 1 to 4 carbons or phenyl;
R.sub.18 is lower alkyl of 1 to 4 carbons;
n is zero or one;
R.sub.2 is aryl-CH.sub.2 --, substituted aryl-CH.sub.2 --, heteroaryl-CH.sub.2 --, or straight or branched chain alkyl of 1 to 7 carbons; and
R.sub.19 is hydrogen.

14. A compound of the formula: ##STR80## including a pharmaceutically acceptable salt thereof wherein: R.sub.1 is hydrogen or ##STR81## R.sub.2 is hydrogen, alkyl, cycloalkyl-(CH.sub.2).sub.m --, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.p --;

n is zero or one;
m is zero or an integer from 1 to 6;
p is an integer from 1 to 6;
R.sub.3 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.m --;
X.sub.1 is ##STR82## R.sub.10 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.p --, or substituted aryl-(CH.sub.2).sub.p --;
R.sub.12 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.m --, or substituted aryl-(CH.sub.2).sub.m --;
Y.sub.1 is O, S;
b is zero or one;
the term "alkyl" refers to straight and branched chain radicals having one to seven carbon atoms;
the term "cycloalkyl" refers to saturated rings of 4 to 7 carbon atoms;
the term "substituted alkyl" refers to such straight and branched chain radicals having to 1 to 7 carbon atoms wherein one or more hydrogens have been replaced by a hydroxy, amino, halo, trifluoromethyl, --NH(lower alkyl of 1 to 4 carbons), --N(lower alkyl of 1 to 4 carbons).sub.2, lower alkoxy of 1 to 4 carbons, or lower alkylthio of 1 to 4 carbons;
the term "aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl;
the term "substituted aryl" refers to phenyl, 1-naphthyl and 2-naphthyl having a substituent selected from lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl of 1 to 4 carbons), and --N(lower alkyl of 1 to 4 carbons).sub.2, and di- and tri-substituted phenyl, 1-naphthyl, and 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino; and
the term "heteroaryl" refers to unsaturated monocyclic rings of 5 of 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms is four or less and all other atoms in the ring are C and bicyclic rings wherein the five or six membered ring as defined above is fused to a phenyl or pyridyl ring, said heteroaryl ring is attached by way of an available carbon or nitrogen atom; and said monocyclic or bicyclic ring can be substituted at an available carbon atom by a lower alkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can be substituted at an available nitrogen atom by benzyloxymethyl, p-toluene sulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl, or benzhydryl.

15. A compound of the formula (I) ##STR83## and pharmaceutically acceptable salts thereof wherein: R.sub.1 is hydrogen, ##STR84## or R.sub.18 --S--; R.sub.2 and R.sub.19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl-(CH.sub.2).sub.m --, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --;

n is zero or one provided that n must be zero when R.sub.2 and R.sub.19 are both other than hydrogen;
m is zero or an integer from 1 to 6;
R.sub.3 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.m --;
R.sub.18 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, heteroaryl-(CH.sub.2).sub.m -- or --S--R.sub.18 completes a symmetrical disulfide wherein R.sub.18 is of the formula (II) ##STR85## X.sub.1 is of the formula (VI) ##STR86## (VII) ##STR87## R.sub.6 and R.sub.10 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --;
R.sub.7 and R.sub.11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m -- or R.sub.6 and R.sub.7 taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons;
b is zero or one;
s is zero, one or two;
Y.sub.1 is --O-- ##STR88## Y.sub.4 is --O--; R.sub.12 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, heteroaryl-(CH.sub.2).sub.m --, ##STR89## R.sub.14 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R.sub.15 is hydrogen, lower alkyl, lower alkoxy or phenyl;
R.sub.16 is lower alkyl or aryl-(CH.sub.2).sub.m --;
the term "alkyl" refers to straight and branched chain radicals having one to seven carbon atoms;
the term "substituted alkyl" refers to such straight or branched chain radicals of 1 to 7 carbons wherein one or more hydrogens have been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.2, lower alkoxy, lower alkylthio or carboxy;
the term "alkenyl" refers to straight or branched chain radicals of 3 to 7 carbon atoms having one or two double bonds;
the term "substituted alkenyl", refers to such straight or branched radicals of 3 to 7 carbons having one or two double bonds wherein a hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.2, lower alkoxy, lower alkylthio, or carboxy;
the term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms;
the term "aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl;
the term "substituted aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl having a substituent selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl), and --N(lower alkyl).sub.2, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino;
the term "heteroaryl" refers to unsaturated monocyclic rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms is four or less and all other atoms in the ring are C and bicyclic rings wherein the five or six membered ring as defined above is fused to a phenyl or pyridyl ring, said heteroaryl ring is attached by way of an available carbon or nitrogen atom; and said monocyclic or bicyclic ring can be substituted at an available carbon atom by lower alkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can be substituted at an available nitrogen atom by benzyloxymethyl, p-toluene sulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl or benzhydryl;
the term "lower alkyl" refers to straight or branched chain radicals having one to four carbons;
the term "substituted lower alkyl" refers to such straight or branched chain radicals having one to four carbons wherein one hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.2, lower alkoxy, lower alkylthio, or carboxy;
the terms "lower alkoxy" and "lower alkylthio" refer to such lower alkyl groups as defined above attached to an oxygen or sulfur; and
the term "halo" refers to chloro, bromo, fluoro, and iodo.
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Patent History
Patent number: 5859239
Type: Grant
Filed: Sep 30, 1997
Date of Patent: Jan 12, 1999
Assignee: E. R. Squibb & Sons, Inc. (Princeton, NJ)
Inventors: Donald S. Karanewsky (Escondido, CA), Jeffrey A. Robl (Newtown, PA)
Primary Examiner: Mukund J. Shah
Assistant Examiner: Bruck Kifle
Attorney: Stephen B. Davis
Application Number: 8/941,469
Classifications
Current U.S. Class: The Chalcogen And The Nitrogen Are In The 1,5-positions Of The Bicyclo Ring System (e.g., 1,5-benzothiazepinone, Etc.) (540/491)
International Classification: C07D26702; C07D28102;